title: Glucose promotes breast cancer aggression and reduces metformin efficacy.
abstract: Metformin treatment has been associated with a decrease in breast cancer risk and improved survival. Metformin induces complex cellular changes, resulting in decreased tumor cell proliferation, reduction of stem cells, and apoptosis. Using a carcinogen-induced rodent model of mammary tumorigenesis, we recently demonstrated that overfeeding in obese animals is associated with a 50% increase in tumor glucose uptake, increased proliferation, and tumor cell reprogramming to an "aggressive" metabolic state. Metformin significantly inhibited these pro-tumorigenic effects. We hypothesized that a dynamic relationship exists between chronic energy excess (glucose by dose) and metformin efficacy/action. Media glucose concentrations above 5 mmol/L was associated with significant increase in breast cancer cell proliferation, clonogenicity, motility, upregulation/activation of pro-oncogenic signaling, and reduction in apoptosis. These effects were most significant in triple-negative breast cancer (TNBC) cell lines. High-glucose conditions (10 mmol/L or above) significantly abrogated the effects of metformin. Mechanisms of metformin action at normal vs. high glucose overlapped but were not identical; for example, metformin reduced IGF-1R expression in both the HER2+ SK-BR-3 and TNBC MDA-MB-468 cell lines more significantly at 5, as compared with 10 mmol/L glucose. Significant changes in gene profiles related to apoptosis, cellular processes, metabolic processes, and cell proliferation occurred with metformin treatment in cells grown at 5 mmol/L glucose, whereas under high-glucose conditions, metformin did not significantly increase apoptotic/cellular death genes. These data indicate that failure to maintain glucose homeostasis may promote a more aggressive breast cancer phenotype and alter metformin efficacy and mechanisms of action.
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Reema
authors.initials: R
authors.lastname: Wahdan-Alaswad
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Zeying
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Edgerton
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Surgery; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Deng
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA; Department of Molecular Medicine; Aarhus University; Aarhus, Denmark.
authors.forename: Sigrid Salling
authors.initials: SS
authors.lastname: Arnadottir
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, CO USA.
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D005947:Glucose
keywords: breast cancer; glucose; metabolism; metformin; therapy